Drug composition

ABSTRACT

Drug composition having antirheumatic and analgesic indications containing as active ingredients dextro-propoxyphene and phenyl butazone, and treatment comprising administering as active ingredients dextro-propoxyphene and phenyl butazone.

United States Patent 1 1 1111 3,890,444

Wawretschek June 17, 1975 [54] DRUG COMPOSITION 3,749,797 7/1973 Miller424/308 [75] Inventor: Helmuth Wawretschek, Friesoythe, FOREIGN PATENTSOR APPLICATIONS Germany 1,081,105 8/1967 United Kingdom [73] Assignee:Servomed Arzneimittel Gmbl'l, OTHER PUBLICATIONS Oldenburg, GermanyFiled: p 1973 Amer can Drug Index (I972) p. 174. pp 58 PrimaryExaminer--Stanley J. Friedman Attorney, Agent, or Firm-Robert R. Priddy;Burton [30] Foreign Application Priority Data Amermck 1' Apr. 26, 1972Germany 2220500 [57] ABSTRACT I [52] US. Cl 424/273; 424/311 Drugcomposition having antirheumatic and analgesic [51] Int. Cl A6lk 27/00indications containing as active ingredients dextro [58] Fleld of Search424/273 propoxyphene and phenyl butazone and treatment comprisingadministering as active ingredients dextro- [56] References cuedpropoxyphene and phenyl butazone.

UNITED STATES PATENTS 6 Cl N D 3,482,021 12/1969 Gosling 424/273 'awmgsDRUG COMPOSITION t The present invention relates to a drug compoundantirheumatic and analgesic indication.

It has been known, following the synthesis by H. Stenzel in 1946, thatphenyl butazone (1,2-diphenyl- 3,5-dioxo-4-n-butyl-pyrazolidine) hasanalgesic and antirheumatic effects. Until the present time, phenylbutazone was considered to be the most effective antirheumatic drug,apart from the steroids. However, the administration of phenyl butazonein effective dosages is accompanied by serious side effects, caused byits inhibiting action on certain enzymatic reactions taking place in thebody.

It is also known that these side effects can be avoided by using acombination of a reduced dosage of phenyl butazone with an analgesic.

From British Pat. No. 1,081,105 is known a drug which hasanti-inflammatory and analgesic effects and which consists of acombination of butazone l-phenyl- 3,5-dioxo-4-n-butyl-butazolidine) andd-propoxyphene (1,2diphenyl-2-propionoxy-3-methyl-4-dimethylaminobutazone hydrochloride), the analgesic effect of thed-propoxyphene component being magnified through its combination withbutazone. From this patent disclosure it is further known that this kindof magnification effect is not obtainable with combinations of phenylbutazone with propoxyphene, and that these combinations are thereforenot suitable for medication. Yet, there has existed a long-standingbasic need for such a combination, especially of phenyl butazone becauseof its very strong antirheumatic indication in comparison to butazone,with analgesic agents in which the magnifying characteristics would bepresent.

In the past, the magnifying effects of phenyl butazone have beenobtained only in combination with such drugs as morphine, codeine, ormethadone. However, these combinations have the drawback that theyinvolve the risk of patient addiction, and for this reason they are notvery desirable.

The objective underlying the present invention was therefore thediscovery of a drug based on phenyl butazone which retains the knownantirheumatic effects of phenyl butazone, while having a stronganalgesic indication at reduced dosage, so that the known side effectsare eliminated, or at least reduced.

In spite of the commonly held belief that combinations of phenylbutazone with propoxyphene are not suitable for medication purposes, theabove objective has now been unexpectedly attained by the discovery of adrug compound consisting of phenyl butazone and dextro-propoxyphene.

The simultaneous administration of phenyl butazone anddextro-propoxyphene was found to produce an extraordinar'ily pronouncedmagnification of the analgesic-effects, in addition to a prolongation ofthe analgesia itself. It has thus become possible to make thetherapeutic dosages of the active ingredients in the drug compound smallenough to substantially eliminate the known side'effects. I

In the following the invention will be explained in more detail withreference to several embodiments.

In a series of writhing tests performed on mice it was found thatespecially favorable results are obtained with a drug compound in whichdextro-propoxyphene and phenyl butazone are present in a molar ratio ofl to 2. These results are reflected in a table given below in which someof the readings obtained in the tests are listed by way of example. Theeffectiveness of the different drug compounds is stated as a percentagein relation to the l to 2 molar ratio.

Table l Reciprocal values of ED values of various mixtures ofdextro-propoxyphene-HCL with phenyl butazone, given as a percentage ofthe ED value of a mixture with a molar ratio of l to 2, which is equalto 100 percent (writhing test on mice):

Molar ratio: 45 min 90 min d-propoxyphene to phenyl butazone l to 16 57l to 8 8l 7c 1 to 4 94 7c 97 l to 2 100 100 70 l to l 74 7b 98 7ctropropoxyphene with phenyl butazone when compared to dextropropoxyphenealone (A), produced an analgesia magnification of up to 4.2-fold, asshown by a comparison between the ED values of (A) and (B), taken 180minutes after oral administration. The values which correspond tovarious other times elapsed are listed in Table 2 below:

Table 2 ED values obtained in writhing tests on mice, at times elapsedbetween 15 and 240 minutes after oral administration of compounds A, C,and B (values for B are computed from readings for C):

Compound 15 30 60 180 240 (A) dextro-propoxyphene 24 23 31 H (B)dextro-propoxyphene l3 1 1 I6 27 32 37 m mixture computed from (C) (C)mixture of dextro- 33 30 53 72 85 97 propoxyphene with phenyl butazone,molar ratio 1 to--2-- (D) phenyl butazone 350 360 390 650 650 900 ED, inmg per kg body weight duration in minutes 3 4 A magnification ofeffectiveness is evident and can Graph 1 also shows another interestingresult with rebe computed from the ED values of Table 2. This spect totherapy: 37 mg of dextro-propoxyphenemagnification is illustrated inGraph I. hydrochloride in pure form are sufficient for an analge- G h Isia lasting approximately 70 minutes, whereas the same rap 5 dosage ofdextro-propoxyphene in the mixture dis- Effectiveness magnificationfactor obtained through closed above assures an equally effectiveanalgesia, mp n of 50 values of and in Table 2 even after 4 hours ofelapsed time (see Graph II).

Magnification factor 5.-

l l l l I l I l l l i 15 so 120 1 240 4 minutes Graph ll D-Pro mixt e 1v I a DProp.-HCL

l l 15 3O 60 v v 240 minute s Table 3 Number of very ineffec-- casesgood good fair tive Degenerative spine syndromes, 197 49 1 I with orwithout radiculitis, I I 19 14 I such as: spondyl-arthrosis morbusBechterew osteochondrosis HWS-syndrome, occipital syndrome, thoracicsyndrome LWS-syndrome, lumbo-sacral syndrome discus prolapse Arthroses44 9 24 9 2 Arthritides 2 31 l 1 Neuralgias, neuritis 46 14 24 5 I 3Abdominal rheumatisms 22 8 l2 2 Periarthritides l4 5 5 2 2Post-traumatic conditions 24 30 l Total 413 111 241 37 24 In 82.2percent of these cases the results observed by the examining physicianswere listed as either very good or good. The extraordinary analgesiceffects achieved are particularly evident in the category ofpost-traumatic conditions. The treatment results obtained in othertypical categories of the rheumatoid group indicates that theantirheumatic effects of phenyl butazone in the disclosed combinationfully match previously observed effects of treatment with phenylbutazone in its known large dosage, even though its dosage in thedisclosed combination is substantially reduced.

It has thus become possible to offer successful antirheumatic therapy,in spite of a reduction of the phenyl butazone dosage to one-third ofits previously required dosage.

I claim:

1. Drug composition having an antirheumatic and analgesic indicationcontaining as active ingredients dextropropoxyphene and phenyl butazonein moleratio between 1 to l and l to 8.

2. The drug composition of claim 1 wherein the mole ratio ofdextro-propoxyphene to phenyl butazone is between 1 to l and 1 to 4.

3. The drug composition of claim 1 wherein the mole ratio ofdextro-propoxyphene to phenyl butazone is l 4. The method of treatingrheumatic disorder which

1. Drug composition having an antirheumatic and analgesic indicationcontaining as active ingredients dextropropoxyphene and phenyl butazonein mole ratio between 1 to 1 and 1 to
 8. 2. The drug composition ofclaim 1 wherein the mole ratio of dextro-propoxyphene to phenyl butazoneis between 1 to 1 and 1 to
 3. The drug composition of claim 1 whereinthe mole ratio of dextro-propoxyphene to phenyl butazone is 1 to
 2. 4.THE METHOD OF TREATING RHEUMATIC DISORDER WHICH COMPRISES ADMINISTERINGTO A PATIENT SUFERING FROM RHEUMATIC DISORDER AN EFFECTIVE ANTIRHEUMATICAND ANALGESIC AMOUNT OF DEXTRO-PROPOXYPHENE AND PHENYL BUTAZONE IN MOLERATIO BETWEEN 1 TO 1 AND 1 TO 8 AS ACTIVE INGREDIENTS.
 5. The process ofclaim 4 wherein the mole ratio of dextro-propoxyphene to phenyl butazoneis between 1 to 1 and 1 to
 4. 6. The process of claim 4 wherein the moleratio of dextro-propoxyphene to phenyl butazone is 1 to 2.